The development of vascular grafts and medical devices that contact physiological fluids, particularly blood, is a rapidly developing area of medicine. This has been hampered, however, by the lack of suitable synthetic materials that are stable when contacted with such fluids.
Adverse reactions between materials and blood components are predominant factors limiting the use of synthetic materials that come into contact with physiological fluids. For example, catheters, vascular grafts, and the like, tend to serve as a nidus, or focus, for the formation of thrombi (blood clots). Initial contact of such materials with blood results in deposition of plasma proteins, such as albumin, fibrinogen, immunoglobulin, coagulation factors, and complement components. The adsorption of fibrinogen onto the surface of the material causes platelet adhesion, activation, and aggregation. Other cell adhesive proteins, such as fibronectin, vitronectin, and von Willebrand factor (vWF) also promote platelet adhesion. As a result, the continual use of anticoagulants in conjunction with the introduction of such materials to the body is often necessary.
Furthermore, complement activation occurs when materials are introduced into blood. Adsorption of large amounts of IgG, IgM, and C3b onto surfaces causes activation. Subsequently, complexes may be formed which contribute to undesirable immune responses, such as proteolysis, cell lysis, opsonization, anaphylaxis, and chemotaxis. As a result, these responses render such materials incompatible with the living body.
A number of approaches have been suggested to improve the biocompatibility, and even blood compatibility, of medical devices. One approach has been to modify the surface of the material to prevent undesirable protein adhesion by providing the material with a low polarity surface, a negatively charged surface, or a surface coated with biological materials, such as enzymes, endothelial cells, and proteins. Another approach has been to bind anticoagulants to the surface of biologically inert materials to impart antithrombogenic characteristics to the materials. Still another approach used in the art has been the copolymerization of various phospholipids which are used as coating materials for various substrates. Partial polymeric backbone coatings have also been used in a similar fashion. However, many of these methods can result in a leaching or "stripping off" of the coating.
Some approaches require amination of the substrate surface. For example, U.S. Pat. No. 5,342,693 (Winters et al.) teaches that a siloxane surface must first be functionalized (e.g., with amine groups) in order to attach biomolecules. Additionally, quaternary amines have been bound to polymer surfaces, followed by the binding of heparin thereto. Conversely, heparin has been complexed with a quaternary amine prior to coating the complex onto a polymeric surface. Both of these methods have the disadvantage of being nonpermanent or leachable systems, i.e., the heparin would gradually be lost from the polymer material into the surrounding medium. Furthermore, coated systems generally have limited viability due to the instability of the anticoagulant.
Thus, a need exists for a blood compatible material for use in medical devices that retains antithrombogenic properties, i.e., reduced platelet adhesion and activation, for an extended period of time.